tbuckley/cabot-search huggingface dataset:
Geographic variation in utilization of doublet therapy for metastatic prostate cancer.
Authors: Samuel L. Washington, Janet E. Cowan, Shoujun Zhao, Jennifer Rider, Nicholas Taylor, Warren Whyte, Peter Carroll, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2023)

41 Background: Clinical trials for men with metastatic prostate cancer have supported the use of combination therapies to improve survival outcomes, with recent work showing increased benefit of triplet regimens. However, real-world utilization of doublet therapy ( i.e., androgen deprivation therapy (ADT) plus a novel hormonal therapy (NHT)) and variation in use according to geographic region have not been evaluated in detail. With recent data supporting the use of triplet regimens we must understand what factors already impact doublet therapy utilization before we can intensify treatment further. Using data aggregated from a national cohort of community and academic medical oncology practices, we characterized real-world utilization of doublet therapy and examined factors associated with its use, including geographic region. Methods: Using ConcertAI RWD, clinical data of men with metastatic prostate cancer was linked with state-level measures of socioeconomic factors and healthcare resources from the Area Health Resources File. Logistic regression was used to evaluate associations between clinical and community characteristics and receipt of doublet therapy (vs ADT alone) within 90 days of diagnosis; models were adjusted for clinical factors, state level factors (excluding hospital beds, poverty, and education due to collinearity), and geographic region. Odds ratios (ORs) with 95% confidence intervals were reported. Results: A total of 1,763 men with M1 disease were eligible, with a mean age of 68.6 years at diagnosis. Nearly half (48%) lived in the Southern region, 9.3% in North East, 18.6% in West, and 23.7% in Midwest. Roughly 13.8% were Black, and 1.3% American Indian, and 1.1% Asian. One-third received ADT alone (37.8%). Regression analysis for ADT+NHT vs. ADT included 1,604 men, of which 84.6% received doublet therapy. Geographic region [vs Southern: Midwest, OR 0.6, 95% CI 0.4-0.9; Northeast, OR 0.4, 95% CI 0.2-0.7], larger state population [(log-transformed) OR 0.09, 95 % 0.02-0.3], prior surgery or radiation (vs none, OR 1.7, 95% CI 1.3-2.3), greater urologist density [(log-transformed), OR 0.1, 95% CI 0.02-0.8] and radiation oncologist density [(log-transformed), OR 12.9, 95% CI 2.8-60.2] were significantly associated with receipt of doublet therapy compared to ADT alone. Conclusions: Receipt of doublet therapy was impacted by geographic region and regional availability of specialty care (i.e. urologist and radiation oncologist density), emphasizing the relationship between regional medical expertise and care implementation. As the drive to improve care grows, our study highlights how treatment remains influenced by where you live and the need for identifying actionable targets for intervention and organizational change at the regional level.
Clinical significance of squamous differentiation in upper tract urothelial carcinoma treated with radical nephroureterectomy.
Authors: Akinori Minato, Hirotsugu Noguchi, Rieko Kimuro, Ikko Tomisaki, Kenichi Harada, Naohiro Fujimoto
Journal: Journal of Clinical Oncology (2023)

451 Background: Upper tract urothelial carcinoma (UTUC) involving the renal pelvis/ureter is histologically similar to bladder cancer in morphological diversity. Although squamous differentiation (SD) is the most common variant in UTUC, the clinical significance of SD in UC has yet to be comprehensively elucidated given the rarity of the disease compared to bladder cancer. To assess the impact of SD on the prognosis of patients with UTUC undergoing radical nephroureterectomy (RNU). Methods: Among the 244 consecutive patients who underwent RNU at our single institution from May 2005 to October 2019, only patients who had histologically confirmed pure UC or UC with SD (UCSD) were included. SD required the presence of intercellular bridges or keratinization for diagnosis. Metastasis-free survival (MFS) and overall survival (OS) rates were retrospectively evaluated using Kaplan–Meier analysis and Cox regression analysis. Results: We identified 197 (87.9%) and 27 (12.1%) patients with pure UC and UCSD, respectively. No significant differences in age, sex, concomitant carcinoma in situ and tumour grade were observed between the groups. UCSD was significantly associated with an advanced tumour stage and a higher rate of lymphovascular invasion. With a median follow-up time of 58 months, the pure UC and UCSD groups had a 5-year MFS rate of 65.2% and 40.9% ( p=0.005) and a 5-year OS rate of 74.4% and 49.0% ( p=0.002), respectively. Multivariate analyses revealed that the presence of SD was significantly associated with MFS [hazard ratio (HR), 1.88; p=0.027] and OS (HR, 1.70; p=0.048). Conclusions: The patients with UCSD are at high risk for disease metastasis and short-term survival. SD in UC could be an independent predictor of poor prognosis after RNU for UTUC.
Overall survival, efficacy, and safety outcomes beyond front-line modern therapies in metastatic clear-cell renal cell carcinoma.
Authors: Jordyn Kreutzfeldt, Mavis Obeng-Kusi, Ricardo J. Estrada-Mendizabal, Briana M Choi, Ivo Abraham, Alejandro Recio-Boiles
Journal: Journal of Clinical Oncology (2023)

667 Background: Due to the ever-changing front-line landscape therapeutic options for m-ccRCC, the second-line (2L) treatment decision remains challenging due to limited information comparing each of the options. We present a survival, efficacy, and safety comparison of the 2L treatment regimens based on the most recent drug approvals for m-ccRCC. Methods: Inclusion criteria for our NMA included phase II/III RTCs that evaluated 2L and beyond for metastatic ccRCC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE) hazard ratios (HRs), odds ratios (OR), and 95% confidence intervals (CI) of the treatment differences were abstracted. The p-scores were used to rank treatments. Data were analyzed in a fixed effects model using the netmeta package in R v.1.5-0. Results: Nine studies with 10 therapies included demonstrated some level of efficacy over placebo (Table). Pairwise comparisons using the NMA matrix revealed no differential OS benefit between axitinib (A), cabozantinib (C), lenvatinib+everolimus (LE), and nivolumab (N). Other regimens had no OS benefit when compared to placebo. Table was ordered based on p-score ranking the certainty that one treatment is better than another averaged over all competing treatments for OS. Placebo represents the reference of 1. Conclusions: LE had the lowest safety profile, although did prove to have the best OS and efficacy based on PFS/ORR. C and N, both had significant improvement in OS and efficacy over placebo with lower rates of SAEs compared to LE. Therefore, while further direct comparison studies are warranted to inform clinical practice, for now, we rely on the limitations inherent in indirect treatment comparisons of a NMA. [Table: see text]
Radiation therapy and irreversible electroporation for intermediate risk prostate cancer (RTIRE).
Authors: Timothy D McClure, Karla V. Ballman, Ariel E. E. Marciscano, Christopher Barbieri, Himanshu Nagar
Journal: Journal of Clinical Oncology (2023)

TPS403 Background: The objective of the RTIRE clinical trial (NCT05345444) is to demonstrate the feasibility, safety, and early oncologic efficacy of combining MRI-guided stereotactic body radiation therapy (MRgSBRT) with irreversible electroporation (IRE) for men with intermediate-risk localized prostate cancer. Methods: Inclusion criteria: 1) Men aged ≥18, 2) ECOG 0 –1, 3) Histologically confirmed intermediate risk prostate cancer per NCCN guidelines, 4) Focal grade group 2 (GG2) or 3 (GG3) cancer in multi-parametric magnetic resonance imaging (mpMRI) target, 5) Gland size &lt; 80cc, 6) Ability to undergo IRE, 7) Ability to receive MRI-guided SBRT, 8) Ability to complete the HRQOL assessment surveys, 9) Willingness to undergo 12 month follow up biopsy. Exclusion criteria: 1) Prior TURP, 2) Prior history of focal therapy, 3) Prior history of receiving pelvic radiotherapy, 4) Patient with history of inflammatory bowel disease, 5) History of bladder neck or urethral stricture. Study Design/Endpoints: This is a feasibility and safety study assessing the ability to perform IRE followed by real-time MRgSBRT. Subjects will undergo focal IRE followed by MRgSBRT (&gt;6 weeks after IRE) to the prostate +/- seminal vesicles prescribed to 32.5 Gy in 5 fractions. The primary endpoint of the first portion of the trial is feasibility, defined as at least 80% of subjects (8 of 10 subjects) undergoing assessment at 12-weeks post-IRE and at 6-weeks post-MRgSBRT within 1 year from enrollment of the first subject. The expansion phase will include an additional 40 subjects to assess side effect profile and early oncologic efficacy (n=50) at 12 months post RTIRE. RTIRE has enrolled 8 subjects in 3 months and will proceed to the expansion phase. Secondary endpoints include: 1) short-term safety as measured by treatment-related adverse events, 2) oncologic efficacy as measured by number of subjects with presence of ≥GG2 cancer at 12 months post-RTIRE therapy, 3) health-related quality of life (HRQOL) as measured by Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) 4) post-RTIRE prostate-specific antigen (PSA) kinetics including time to PSA nadir and post-nadir PSA stability, 5) assessment of pre and post-RTIRE mpMRI changes to evaluate the area of necrosis and presence of residual tissue, 6) rates of biochemical and clinical progression and the need for secondary or adjuvant treatment following RTIRE. Clinical trial information: NCT05345444 .
Contemporary analysis of complications after retroperitoneal lymph node dissection: Data from the National Surgical Quality Improvement Program 2006-2018.
Authors: Ellen Cahill, Kevin J Chua, Sai Krishnaraya Doppalapudi, Arnav Srivastava, Hiren V Patel, Vasundhara Balraj, Saum Ghodoussipour, Thomas L Jang
Journal: Journal of Clinical Oncology (2023)

416 Background: Retroperitoneal lymph node dissection (RPLND) offers therapeutic and diagnostic value for patients with testicular cancer. Specific indications for RPLND include management of patients with stage I-II nonseminomatous germ cell tumors (NSGCT), advanced NSGCTs with post-chemotherapy masses, and seminomas with early metastatic disease. While RPLND is an invasive and complex operation, prior research suggests complication rates are relatively low and may vary based on patient characteristics and disease-related factors. We examined the incidence of complications after RPLND and aimed to determine risk factors associated with these complications. Methods: The National Surgical Quality Improvement Program (NSQIP) database from 2006-2018 was queried for RPLND in patients with testis cancer who were identified by ICD 9 and 10 codes. All reported postoperative complications were examined and categorized by type and organ system. Univariable and multivariable logistic regressions were performed to determine risk factors associated with complications. Results: 368 RPLND procedures over the 13 year interval met inclusion criteria. The overall complication rate was 23.91% (n=88). The most common complication was bleeding requiring transfusion (n=59, 16.03%). Risk factors associated with any complication included older age (OR 1.041, p=0.003), longer operative time (OR 1.007, p&lt;0.001), and major concomitant procedure (OR 2.429, p=0.015). As shown in the table, risk factors associated with transfusion included older age (OR 1.040, p=0.019), longer operative time (OR 1.009, p&lt;0.001), and major concomitant procedure (OR 3.296, p=0.004). Higher pre-operative hematocrit was associated with decreased risk of transfusion (OR 0.883, p&lt;0.001). M+ (metastatic) disease and longer operative time were associated with an increased risk for wound, infectious, and respiratory complications. Conclusions: Based on our analysis, almost one in four patients undergoing RPLND experienced a complication. Bleeding requiring transfusion was the most common complication and was associated with patient age, preoperative hematocrit, operative time, and major concomitant procedure. Urologic surgeons may seek to optimize hematocrit prior to surgery, especially when major concomitant procedure may be necessary. [Table: see text]
Therapeutic effect of gedatolisib, a pan-PI3K/mTOR inhibitor, on prostate cancer models with PI3K or PTEN mutational status.
Authors: Adrish Sen, Salmaan A Khan, Ian A. MacNeil, Benjamin E. Rich, Jhomary S Molden, Laura N Davis, Stefano Rossetti, Aaron M Broege, Lance G. Laing
Journal: Journal of Clinical Oncology (2023)

149 Background: Metastatic castration-resistant prostate cancer (mCRPrC) is characterized by a loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K, AKT, and mTOR (PAM) pathway. Loss of the PI3K regulator, PTEN, is frequent during prostate cancer (PrC) initiation, progression, and therapeutic resistance. Co-targeting PAM/AR pathways is a promising PrC treatment strategy but hampered by complex PAM-AR pathway crosstalk driving either reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors (PAM-i) selectively spare (or weakly inhibit) one or more key PAM pathway components, potentiating drug resistance depending on the PAM mutation status of patients. AKT-i demonstrated limited efficacy in PTEN-deficient PrC and even less efficacy in PTEN-wild type (wt) in recent clinical studies, suggesting that more comprehensive inhibition of the PI3K isoforms and mTOR may be required. We posited that gedatolisib, a well-tolerated and potent inhibitor of all Class I PI3K isoforms, mTORC1, and mTORC2, would be effective in both PTEN-wt and PTEN-deficient PrC. Methods: A panel of PrC cell lines with different PI3K or PTEN status ( wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I ( PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). A combination of cell viability, growth rate, cytotoxicity and phospho-FACS analytical assays were used. Xenograft studies evaluating gedatolisib with a subset of these models were also performed in castrated mice. Results: We confirmed that AKT-i is more effective in PTEN-null than PTEN-wt PrC. In contrast, the two pan-PI3K/mTOR-i evaluated were effective independent of PI3K or PTEN status. Gedatolisib exhibited superior potency and efficacy compared to each of the other PAM-i for cell proliferation, death, or PAM pathway activation. In vivo, gedatolisib substantively inhibited tumor growth regardless of PTEN or PI3K status. Conclusions: We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types. In light of the PrC findings reported here, development of gedatolisib may be warranted in PrC patients regardless of their PTEN or PI3K status.
Patient characteristics, treatment patterns and outcomes for patients with renal cell carcinoma in England: A retrospective cohort study using data from the National Cancer Registry and treatment and hospital data.
Authors: Prantik Das, Andrew Clark, Beth Nordstrom, Alison Booth, Poonam Dhokia, Robert Carroll, Luis Vaz
Journal: Journal of Clinical Oncology (2023)

639 Background: Renal cell carcinoma (RCC) is the seventh most common cancer in the UK. It is necessary to examine recent treatment trends and outcomes in England to understand the evolving landscape. The primary aim was to describe the demographic and clinical characteristics of patients with RCC, and assess their overall survival (OS) and treatment duration, overall and by subgroups of interest. Secondly, we aimed to understand use of systemic therapies over time. Methods: This was a retrospective cohort study of patients diagnosed with RCC during 2014-2018 using national registry, treatment and hospital data in England. Descriptive statistics were explored with Chi-squared, Fishers exact and Wilcoxon rank sum tests. OS and treatment duration were analysed using Cox regression models to provide hazard ratios (HR) with 95% CI. Kaplan Meier curves were used to compare the proportion of patients alive or on treatment. Results: The cohort included 32,577 individuals; median age at diagnosis 67 years; 36.6% of patients were female; 81.4% exhibited clear cell histology. RCC diagnosed at stage I-III appeared to increase from 61% in 2015 to 68% in 2018. A total of 5,657 patients received at least 1 line of systemic treatment, decreasing to 2,606 and 989 patients for 2 and 3 treatment lines; at 3 months, treatment persisted for 59.9%, 19.0% and 20.5% respectively. In the cohort, 25,566 (78.5%, 95% CI: 78.0–78.9) were alive 1 year from the date of diagnosis and 21,856, (67%, 95% CI: 66.6–67.6) were alive at 3 years. In the subgroup with metastatic disease, 6,786 (37.1%, 95% CI: 35.9–38.2) were alive at 1 year which decreased to 18.0% (95% CI: 17.06–18.92) at 3 years. Among patients with metastatic disease at initial diagnosis, OS was reduced in those with non-clear cell compared to clear cell RCC (HR: 1.19 [95% CI 1.07-1.33]), and those without nephrectomy had a lower probability of survival compared with those who did have a nephrectomy (HR: 2.54, 95% CI: 2.34–2.75). Conclusions: This study presents the most recent and extensive RCC data from England, examining treatment duration, overall survival and patient demographics at presentation, by histology, metastatic status and line of therapy subgroups. These findings could facilitate exploration of potential unmet needs, inequities of treatment or risk factors for patients.
Study of real-world treatment patterns and adherence to bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Franklin D Gaylis, Bruno Emond, Ameur M Manceur, Anabelle Tardif-Samson, Laura Morrison, Dominic Pilon, Patrick Lefebvre, Lorie Ellis, Hiremagalur parthasarathy Balaji, Andrea Ireland
Journal: Journal of Clinical Oncology (2023)

470 Background: Intravesical BCG is considered a first-line (1L) treatment for high-risk NMIBC patients. Since the presence of carcinoma in situ (CIS) in NMIBC is associated with increased disease progression rates and poor clinical outcomes, BCG is prioritized in clinical guidelines for NMIBC patients with CIS. However, BCG’s US shortage may negatively affect clinical outcomes in patients. This study evaluated the adequacy of BCG treatment patterns among NMIBC patients, including a subgroup with CIS. Methods: Adults with NMIBC treated with BCG were selected from de-identified IBM MarketScan Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Treatment patterns were assessed from the first BCG claim (triggering the start of 1L treatment) until the end of the patient’s observation. Consistent with real-world literature, adequate BCG induction was defined as ≥5 BCG claims within 70 days of the first BCG claim whereas adequate BCG induction and maintenance was defined as ≥7 BCG claims within 274 days of the first BCG claim. Proportions of patients with adequate BCG induction and maintenance were compared between CIS subgroup and overall NMIBC cohorts using chi square tests. Results: Of 5,803 NMIBC patients treated with 1L BCG, 1,182 (20.4%) had documentation of CIS. Overall and CIS cohorts had similar mean age (67 years; range 18-101 years). After 1L BCG, 56.6% and 71.8% of the overall and CIS cohorts had another treatment (P&lt;.001; table). While 86.9% and 90.0% of the overall and CIS cohorts had adequate BCG induction (P=0.003), only 41.5% and 50.8% had adequate BCG maintenance (P&lt;.001). More patients in the CIS versus overall cohort had a cystectomy (13.9% vs 9.7%; P&lt;.001). Conclusions: In this study, most NMIBC patients treated with BCG received adequate induction; however, BCG maintenance was inadequate and most patients had another treatment following 1L BCG. Patients with CIS were more likely to have cystectomy after BCG, suggesting higher risk of progression in this subgroup. Results of this study further emphasize a need for additional available treatment options that are safe, efficacious, and tolerable. [Table: see text]
Early switching to pembrolizumab (Pe) during first-line platinum-based chemotherapy (PCT) in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Yuki Endo, Go Kimura, Jun Akatsuka, Hayato Takeda, Masato Yanagi, Hikaru Mikami, Hiroya Hasegawa, Mami Taniuchi, Akifumi Katsu, Ryota Funato, Yuka Toyama, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2023)

452 Background: With the results of the Javelin bladder 100 trial, PCT followed by ICI has become the standard of care for pts with mUC. While more than half of the pts have progressive disease (PD) by the 4th cycle of PCT, in general, most these pts will receive ICI after 4th cycle of PCT. However, for pts who have PD before 4 cycles, additional PCT will not only be effective, but will also cause side effects and worsen immune environment. However, the outcome of early switching to ICI during 1st-line PCT has not been reported. Here, we investigated whether early switching to Pe may improve prognosis. We also examined the usefulness of serum CYFRA (sCY) as a prognostic marker of 2nd-line Pe in this study. Methods: Seventy pts with mUC received PCT followed by Pe from February 2018 to July 2022 at our institution. Among them 56 pts who had received PCT 3 cycles or less because of PD or unacceptable side effects were included in this study. During PCT, computed tomography (CT) was performed at the end of each cycle and PCT was continued until PD. If PD on CT was confirmed, 2nd-line Pe was initiated. Performance status, metastasis site, neutrophil-lymphocyte ratio, hemoglobin, and serum alkaline phosphatase, C-reactive protein, total protein, albumin, corrected calcium (Ca) and sCY before Pe were examined as possible prognostic factors for overall survival (OS). OS was analyzed by Kaplan-Meier curves and log-rank test. Multivariate analysis on prognostic factors was carried out using the Cox hazards model. Results: Median age was 73 (31-86). Twenty-seven pts (49%) received gemcitabine-cisplatin and 29 (51%) received gemcitabine-carboplatin for PCT. Twelve pts (21%) received 1 cycle of PCT, 2 cycles in 26 (46%) and 3 cycles in 18 (32%). During the median follow-up period of 14.6 (6.2-44.6) months (M), 30 pts (53.5%) had died. The median OS was 15.5M and the 1-year OS rate was 60%. The median PFS was 10.2M and the 1-year PFS rate was 46%. Objective response rate was 25% and 18 pts showed stable disease (32%) and 24 pts (43%) showed PD. On univariate analysis, sCY (p=0.001) and Ca (p=0.003) were the significant factors for OS. On multivariate analysis, sCY (HR 3.2, 95%CI [1.33-7.82], p=0.009) and Ca (HR2.3, (95%CI [1.02-5.22], p=0.046) were the significant factors for OS. Conclusions: Early switching to Pe during 1st-line PCT resulted in PFS of 10.2M and OS of 15.5M, which were longer than those of the KEYNOTE-045 trial (PFS 2M, OS 10M). Early introduction of Pe may be effective in the pts with mUC who are resistant to chemotherapy. sCY and Ca were suggested to be the useful prognostic factors for OS.